Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin.
Intestinal Epithelial Cell-Specific Deletion of PLD2 Alleviates DSS-Induced Colitis by Regulating Occludin.
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DOI：
10.1038/s41598-017-01797-y
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发表时间：
2017-05-08
影响因子：
4.6
通讯作者：
Ryu SH
中科院分区：
文献类型：
--
作者：
Chelakkot C;Ghim J;Rajasekaran N;Choi JS;Kim JH;Jang MH;Shin YK;Suh PG;Ryu SH
溃疡性结肠炎是一种涉及免疫反应失调的多因素疾病。肠上皮屏障的破坏和细菌的移位，导致炎症，在结肠炎中很常见。结肠炎疾病进展过程中上皮屏障功能障碍或紧密连接蛋白调节的潜在机制尚未明确阐明。磷脂酶D（PLD）活性的增加与结肠炎动物模型中的疾病严重程度相关。然而，PLD 2在维持肠屏障完整性中的作用仍然难以捉摸。我们已经产生了结肠特异性Pld 2基因敲除小鼠（Pld 2 IEC KO），以研究结肠炎中肠上皮PLD 2的机制。我们表明，敲除Pld 2赋予对葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的保护。DSS处理诱导结肠上皮细胞中PLD 2的表达并下调occludin。PLD 2被证明介导occludin的磷酸化，并诱导其蛋白酶体降解的c-Src激酶依赖性途径。此外，我们已经表明，用PLD 2抑制剂治疗可以从DSS诱导的结肠炎中拯救小鼠。据我们所知，这是第一份报告表明，PLD 2是关键的上皮紧密连接和闭合蛋白翻转的完整性的调节，从而牵连到结肠炎的发病机制。
Ulcerative colitis is a multi-factorial disease involving a dysregulated immune response. Disruptions to the intestinal epithelial barrier and translocation of bacteria, resulting in inflammation, are common in colitis. The mechanisms underlying epithelial barrier dysfunction or regulation of tight junction proteins during disease progression of colitis have not been clearly elucidated. Increase in phospholipase D (PLD) activity is associated with disease severity in colitis animal models. However, the role of PLD2 in the maintenance of intestinal barrier integrity remains elusive. We have generated intestinal-specific Pld2 knockout mice (Pld2 IEC-KO) to investigate the mechanism of intestinal epithelial PLD2 in colitis. We show that the knockout of Pld2 confers protection against dextran sodium sulphate (DSS)-induced colitis in mice. Treatment with DSS induced the expression of PLD2 and downregulated occludin in colon epithelial cells. PLD2 was shown to mediate phosphorylation of occludin and induce its proteasomal degradation in a c-Src kinase-dependent pathway. Additionally, we have shown that treatment with an inhibitor of PLD2 can rescue mice from DSS-induced colitis. To our knowledge, this is the first report showing that PLD2 is pivotal in the regulation of the integrity of epithelial tight junctions and occludin turn over, thereby implicating it in the pathogenesis of colitis.